Because of the risk for development of skin or hypersensitivity reactions and neuropsychiatric disorders, the European Medicines Agency has recommended that new patient prescriptions should only be to treat sleepiness associated with narcolepsy.[7]

Modafinil has also found off-label use with the neurological fatigue reported by some with multiple sclerosis.[8] In 2000, Cephalon conducted a study to evaluate modafinil as a potential treatment for MS-related fatigue. A group of 72 people with MS of varying degrees of severity tested two different doses of modafinil and an inactive placebo over nine weeks. Fatigue levels were self-evaluated on standardized scales. Participants taking a lower dose of modafinil reported feeling less fatigued and there was a statistically significant difference in fatigue scores for the lower dose versus the placebo. The higher dose of modafinil was not reported to be significantly more effective.[9][10]

Militaries of several countries are known to have expressed interest in modafinil as an alternative to amphetamine—the drug traditionally employed in combat situations where troops face sleep deprivation, such as during lengthy missions. The French government indicated that the Foreign Legion used modafinil during certain covert operations. The United Kingdom's Ministry of Defence commissioned research into modafinil[18] from QinetiQ and spent £300,000 on one investigation.[19] In 2011, the Indian Air Force announced that modafinil was included in contingency plans.[20] The Indian Armed Forces Medical Services is researching its use.

In the United States military, modafinil has been approved for use on certain Air Force missions, and it is being investigated for other uses.[21] As of November 2012, modafinil is the only drug approved by the Air Force as a "go pill" for fatigue management.[22] The use of dextroamphetamine (a.k.a., Dexedrine) is no longer approved.[22] One study of helicopter pilots suggested that 600 mg of modafinil given in three doses can be used to keep pilots alert and maintain their accuracy at pre-deprivation levels for 40 hours without sleep;[23] however, significant levels of nausea and vertigo were observed. A second helicopter study found modafinil was comparable to dextroamphetamine and was well-tolerated.[24] Another study of fighter pilots showed that modafinil given in three divided 100 mg doses sustained the flight control accuracy of sleep-deprived F-117 pilots to within about 27 percent of baseline levels for 37 hours, without any considerable side effects.[25] In an 88-hour sleep loss study of simulated military grounds operations, 400 mg/day doses were mildly helpful at maintaining alertness and performance of subjects compared to placebo, but the researchers concluded that this dose was not high enough to compensate for most of the effects of complete sleep loss.[26]

In law enforcement, tactical paramedics in Maryland (US) may administer 200 mg of modafinil once daily in order to "enhance alertness / concentration" and "facilitate functioning with limited rest periods."[27]

Although a nootropic, Modafinil is less likely than its parent drug, adrafinil, to cause side effects such as stomach pain, skin irritation, anxiety, and (with prolonged use) elevated liver enzymes.[29] The patient should be aware that placebo-controlled clinical trials cannot be used to predict the frequency of adverse experiences in the course of usual medical practice, where patient characteristics and other factors may differ from those occurring during clinical studies. Reported effects from patient control groups during clinical trials include:[30]

Modafinil may induce severe dermatologic reactions requiring hospitalization. From the date of initial marketing, December 1998, to January 30, 2007, FDA received six cases of severe cutaneous adverse reactions associated with modafinil, including erythema multiforme (EM), SJS, TEN, and DRESS involving adult and pediatric patients. The FDA issued a relevant alert. In the same alert, the FDA also noted that angioedema and multi-organ hypersensitivity reactions have also been reported in postmarketing experience.[33]

A National Institute on Alcohol Abuse and Alcoholism (NIAAA) study highlighted "the need for heightened awareness for potential abuse of and dependence on modafinil in vulnerable populations" due to the drug's effect on dopamine in the brain's reward center.[34] However, the synergistic actions of modafinil on both catecholaminergic and histaminergic pathways lower abuse potential as compared to traditional stimulant drugs while maintaining the effectiveness of the drug as a wakefulness-promoting agent. Studies have suggested that modafinil "has limited potential for large-scale abuse"[35] and "does not possess an addictive potential in naive individuals."[36]

In mice and rats, the median lethal dose (LD50) of modafinil is approximately or slightly greater than 1250 mg/kg. Oral LD50 values reported for rats range from 1000 mg/kg to 3400 mg/kg. Intravenous LD50 for dogs is 300 mg/kg. Clinical trials on humans involving taking up to 1200 mg/day for 7 to 21 days and known incidents of acute one-time overdoses up to 4500 mg did not appear to cause life-threatening effects, although a number of adverse experiences were observed, including excitation or agitation, insomnia, anxiety, irritability, aggressiveness, confusion, nervousness, tremor, palpitations, sleep disturbances, nausea, and diarrhea.[4] As of 2004, the FDA is not aware of any fatal overdoses involving modafinil alone (as opposed to multiple drugs, including modafinil).[4] Consequently, oral LD50 of modafinil in humans is not known exactly. However, it appears to be higher than oral LD50 of caffeine. Bastuji and Jouvet describe a suicide attempt using 4500 mg of modafinil; the patient survived with no long-term effects but temporary nervousness, nausea, and insomnia.[37] A similar incident involving a suicide attempt by a 15-year-old female using 5000 mg of the drug (102 mg/kg) was observed in 2008 in Israel; the patient experienced severe headache, nausea, abdominal pain, dyskinesia, insomnia, and mild tachycardia, but no cardiovascular distress or abnormalities in liver and kidney function, and recovered in a few days without any apparent long-term effects.[38]

Modafinil can make certain types of birth control pills less effective, which could result in an unplanned pregnancy.[citation needed] Modafinil in combination with yohimbine causes a dangerous increase in heart rate and blood pressure.[39][non-primary source needed]

Modafinil induces the cytochrome P450 enzymes CYP1A2, CYP3A4, and CYP2B6, as well as inhibiting CYP2C9 and CYP2C19in vitro.[40] It may also induce P-glycoprotein (Pgp), which may affect drugs transported by Pgp, such as digoxin.[citation needed] The bioavailability of modafinil is greater than 80% of the administered dose. In vitro measurements indicate that 60% of modafinil is bound to plasma proteins at clinical concentrations of the drug. This percentage actually changes very little when the concentration is varied.[41] Cmax (peak levels) occurs approximately 2–3 hours after administration. Food slows absorption, but does not affect the total AUC[clarification needed](AUC - area under the curve - meaning, food may slow absorption, but the total amount of the chemical will be absorbed with or without food). Half-life is generally in the 10–12 hour range, subject to differences in CYP genotypes, liver function and renal function. It is metabolized in the liver, and its inactive metabolite is excreted in the urine. Urinary excretion of the unchanged drug ranges from 0% to as high as 18.7%, depending on various factors.[41]

Modafinil's efficacy in improving vigor and well-being in sleep deprivation subjects is dependent on COMT status. Research suggests that individuals with the Val/Val genotype experience a great improvement in their cognitive function, while those with the Met/Met genotype experience very little improvement.[42]

Modafinil and/or its major metabolite, modafinilic acid, may be quantified in plasma, serum or urine to monitor dosage in those receiving the drug therapeutically, to confirm a diagnosis of poisoning in hospitalized patients or to assist in the forensic investigation of a vehicular traffic violation. Instrumental techniques involving gas or liquid chromatography are usually employed for these purposes.[54][55] As of 2011, it is not specifically tested for by common drug screens (except for anti-doping screens) and is unlikely to cause false positives for other chemically-unrelated drugs such as substituted amphetamines.[56]

Modafinil was originally developed in France by neurophysiologist and emeritus experimental medicine professor Michel Jouvet and Lafon Laboratories. Modafinil originated with the late 1970s invention of a series of benzhydryl sulfinyl compounds, including adrafinil, which was first offered as an experimental treatment for narcolepsy in France in 1986. Modafinil is the primary metabolite of adrafinil, lacking the polar -OH group on its terminal amide,[29] and has similar activity to the parent drug but is much more widely used. It has been prescribed in France since 1994 under the name Modiodal, and in the US since 1998 as Provigil.

It was approved for use in the UK in December 2002. Modafinil is marketed in the US by Cephalon Inc., who originally leased the rights from Lafon, but eventually purchased the company in 2001.

Cephalon began to market the R-enantiomer armodafinil of modafinil in the U.S. in 2007. After protracted patent litigation and negotiations (see below), generic versions of modafinil became available in the U.S. in 2012.

U.S. Patent 4,927,855 was issued to Laboratoire L. Lafon on May 22, 1990, covering the chemical compound modafinil. After receiving an interim term extension of 1066 days and pediatric exclusivity of six months, it expired on October 22, 2010. On October 6, 1994, Cephalon filed an additional patent, covering modafinil in the form of particles of defined size. That patent, U.S. Patent 5,618,845 was issued on April 8, 1997, but was reissued in 2002 as RE 37,516, which surrendered the 5618845 patent. With pediatric exclusivity, this patent expired on April 6, 2015.[60][61]

On December 24, 2002, anticipating the expiration of exclusive marketing rights, generic drug manufacturers Mylan, Teva, Barr, and Ranbaxy applied to the FDA to market a generic form of modafinil.[62] At least one withdrew its application after early opposition by Cephalon based on the '516 patent. There is some question whether a particle size patent is sufficient protection against the manufacture of generics. Pertinent questions include whether modafinil may be modified or manufactured to avoid the granularities specified in the new Cephalon patent, and whether patenting particle size is invalid because particles of appropriate sizes are likely to be obvious to practitioners skilled in the art. However, under United States patent law, a patent is entitled to a legal presumption of validity, meaning that in order to invalidate the patent, much more than "pertinent questions" are required.

As of October 31, 2011, U.S. Reissue Patent No. RE 37,516 has been declared invalid and unenforceable.[63] The District Court for the Eastern District of Pennsylvania ruled that RE 37,516 was invalid because it: (1) was on sale more than one year prior to the date of the application in violation of 35 U.S.C. section 102(b); (2) was actually invented by someone else (the French company Laboratoire L. Lafon); (3) was obvious at the time the invention was made to a person having ordinary skill in the art under 35 U.S.C. section 103(a); and (4) failed the written description requirement of 35 U.S.C. section 112.[64] The patent was also found to be unenforceable due to Cephalon's inequitable conduct during patent prosecution.[64]

Cephalon made an agreement with four major generics manufacturers Teva, Barr Pharmaceuticals, Ranbaxy Laboratories, and Watson Pharmaceuticals between 2005 and 2006 to delay sales of generic modafinil in the US until April 2012 by these companies in exchange for upfront and royalty payments.[65] Litigation arising from these agreements is still pending including an FTC suit filed in April 2008.[66]Apotex received regulatory approval in Canada despite a suit from Cephalon's marketing partner in Canada, Shire Pharmaceuticals.[67][68] Cephalon has sued Apotex in the US to prevent it from releasing a genericized armodafinil (Nuvigil).[69] Cephalon's 2011 attempt to merge with Teva was approved by the FTC under a number of conditions, including granting generic US rights to another company;[70] ultimately, Par Pharmaceutical acquired the US modafinil rights as well as some others.[71]

In the United Kingdom, Mylan Inc. received regulatory approval to sell generic modafinil produced by Orchid in January 2010; Cephalon sued to prevent sale, but lost the patent trial in November.[72]

Modafinil is currently[update] classified as a Schedule IV controlled substance under United States federal law; it is illegal to import by anyone other than a DEA-registered importer without a prescription.[73] However, one may legally bring modafinil into the United States in person from a foreign country, provided that he or she has a prescription for it, and the drug is properly declared at the border crossing. U.S. residents are limited to 50 dosage units (i.e., pills).[74] Under the US Food and Drug Act, drug companies are not allowed to market their drugs for off-label uses (conditions other than those officially approved by the FDA);[75] Cephalon was reprimanded in 2002 by the FDA because its promotional materials were found to be "false, lacking in fair balance, or otherwise misleading".[76] Cephalon pled guilty to a criminal violation and paid several fines, including $50 million and $425 million fines to the U.S. government in 2008.[77][78]

The following countries do not classify modafinil as a controlled substance:

Currently, use of modafinil is controversial in the sporting world, with high-profile cases attracting press coverage since several prominent American athletes have tested positive for the substance (see modafinil as a doping agent). Some athletes who were found to have used modafinil protested that the drug was not on the prohibited list at the time of their offenses. However, the World Anti-Doping Agency (WADA) maintains that it was related to already banned substances. The Agency added modafinil to its list of prohibited substances on August 3, 2004, ten days before the start of the 2004 Summer Olympics.

Modafinil has received some publicity in the past when several athletes (such as sprinter Kelli White in 2004, cyclist David Clinger[82] and basketball player Diana Taurasi[83] in 2010) were discovered allegedly using it as a performance-enhancing doping agent. (Taurasi and another player, Monique Coker, tested at the same lab, were later cleared.[84]) It is not clear how widespread this practice is. The BALCO scandal brought to light an as-yet unsubstantiated (but widely published) account of Major League Baseball's all-time leading home-run hitter Barry Bonds' supplemental chemical regimen that included modafinil in addition to anabolic steroids and human growth hormone.[85] Modafinil has been shown to prolong exercise time to exhaustion while performing at 85% of VO2max and also reduces the perception of effort required to maintain this threshold.[86] Modafinil was added to the World Anti-Doping Agency "Prohibited List" in 2004 as a prohibited stimulant (see Modafinil Legal Status).

Modafinil was shown to be an effective treatment for ADHD with a more favorable overall side effect profile to approved treatments in clinical trials, but those trials also produced non-fatal cases of Stevens–Johnson syndrome rashes.[87] The U.S. Food and Drug Administration approval for attention deficit hyperactivity disorder (ADHD) in children was rejected in 2006 due to concerns about rashes. [88] The label for modafinil says that the drug is not approved for use in children and recommends keeping the drug out of the reach of children.[4]

Modafinil used alone has been reported to be effective in a subgroup of individuals with depersonalization disorder; the subgroup of people with depersonalization disorder most likely to respond are those who have attentional impairments, under-arousal, and hypersomnia. However, clinical trials have not been conducted.[89] Dr. Evan Torch calls a combination of an SSRI and modafinil "the hidden pearl that can really help depersonalization disorder."[90]

A randomizeddouble-blind study of modafinil showed that normal healthy volunteers between the ages of 30-44 showed general improvement in alertness as well as mood. In the three-day study, counterbalanced, randomized, crossover, inpatient trial of modafinil 400 mg was administered as well as a placebo to the control group. The conclusion demonstrated that modafinil may have general mood-elevating effects in particular for the adjunctive use in treatment-resistant depression.[17]

Modafinil is under investigation as a possible method to treat cocaine dependence, for several reasons involving biochemical mechanisms of the two drugs, as well as the observation that clinical effects of modafinil are largely opposite to symptoms of cocaine withdrawal.

The pilot 8-week double-blind study of modafinil for cocaine dependence (2004) produced inconclusive results. The number of cocaine-positive urine samples was significantly lower in the modafinil group as compared to the placebo group in the middle of the trial, but by the end of the 8 weeks the difference stopped being significant. Even before the treatment began, the modafinil group had lower cocaine consumption further confounding the results. As compared to placebo, modafinil did not reduce cocaine craving or self-reported cocaine use, and the physicians ratings were only insignificantly better.[102] Dan Umanoff, of the National Association for the Advancement and Advocacy of Addicts, criticized the authors of the study for leaving the negative results out of the discussion part and the abstract of the article.[103][104]

A later double-blind study of modafinil in people seeking treatment for cocaine dependence found no statistically significant effect on the rate of change in percentage of cocaine non-use days, but noted a significant improvement in some secondary outcomes such as the maximum number of consecutive non-use days for cocaine.[105]

Studies on modafinil (even those on healthy weight individuals) indicate that it has an appetite reducing/weight loss effect.[106][107][108][109][110] All studies on modafinil in the Medline database that are for one month or longer which report weight changes find that modafinil users experience weight loss compared to placebo.[111] In 2008, one small-scale study on individuals performing simulated shift work quantified the effect as an 18% decrease in total caloric intake on 200 mg/day, and a 38% decrease on 400 mg/day.[112]

However, the prescribing information for Provigil notes that "There were no clinically significant differences in body weight change in patients treated with Provigil compared to placebo-treated patients in the placebo-controlled clinical trials."[113]

In experimental studies, the appetite reducing effect of modafinil appears to be similar to that of substituted amphetamines, but, unlike substituted amphetamines, the dose of modafinil that is effective at decreasing food intake does not significantly increase heart rate. Also, an article published in the Annals of Clinical Psychiatry, presented the case of a 280-pound patient (BMI=35.52) who lost 40 pounds over the course of a year on modafinil (to 30.44 BMI). After three years, his weight stabilized at a 50-pound weight loss (29.59 BMI). The authors conclude that placebo controlled studies should be conducted on using modafinil as a weight loss agent.[107] Conversely, a US patent (#6,455,588) on using modafinil as an appetite stimulating agent has been filed by Cephalon in 2000.

It is has been studied as a possible treatment for delayed sleep phase syndrome, which causes excessive daytime somnolence when the natural (delayed) diurnal rhythm is replaced by a socially determined earlier or forward shifted sleep schedule.[114]

Modafinil has been used off-label in trials with people with symptoms of post-chemotherapy cognitive impairment, also known as "chemobrain", but in 2011 it was found to be no better than placebo.[121] As of 2011 there was no evidence to support using it to reduce fatigue in palliative care.[122]

^"Cephalon executives have repeatedly said that they do not condone off-label use of Provigil, but in 2002 the company was reprimanded by the FDA for distributing marketing materials that presented the drug as a remedy for tiredness, "decreased activity" and other supposed ailments. In 2008, Cephalon paid $425m and pleaded guilty to a federal criminal charge relating to its promotion of off-label uses for Provigil and two other drugs." http://www.law360.com/articles/127434[verification needed]